1. Field of the Invention
The present invention relates to methods and compositions for treating immune complex associated diseases, preferably systemic lupus erythematosus (SLE), and other systemic autoimmune diseases associated with the subject having aberrant Toll-like receptor (TLR)/B cell receptor (BCR) dual engagement (in B cells) or TLR/Fc gamma receptor dual engagement (in dendritic cells and/or macrophages).
2. Background
Autoimmune diseases are a fairly common but poorly understood group of diseases in which an individual's immune system either 1) begins recognizing self antigens as foreign and starts destroying tissues expressing such antigens thereby causing a disease, or 2) forms immune complexes with these antigens which then deposit in tissues and cause inflammatory pathology. Such autoimmune diseases include, for example, diabetes wherein the immune system turns against and destroys insulin producing pancreatic islet cells; multiple sclerosis, wherein the target antigen is the myelin sheath protecting neurons leading to destruction of function of motorneurons; psoriasis, where the target of the immune system is skin; rheumatoid arthritis, where the target organ is cartilage; and systemic lupus erythematosus (SLE), which presents itself as targeting a variety of tissues with no apparent specificity or selectivity although the target antigens themselves are extremely consistent and characteristic. Because the mechanisms leading to the development of autoimmune diseases in general are mostly unknown, their treatment is often directed to generally suppressing the immune system. Such general immunosuppressive therapies often cause a variety of undesirable side effects including cancer, infertility, and increased susceptibility to infections by viruses, fungi, yeast, and bacteria Therefore, it would be desirable to understand the mechanisms that cause the immune system to turn against self antigens to enable development of more specific therapies for the treatment of the autoimmune diseases.
An example of a poorly understood autoimmune disease is systemic lupus erythematosus (SLE), commonly known as Lupus. SLE is characterized by dysregulation of the immune system resulting in the production of antinuclear antibodies, the generation of circulating immune complexes, and the activation of the complement system. The immune complexes build up in the tissues and joints causing inflammation, and degradation to both joints and tissues. While the word “systemic” correctly suggests that the disease affects the entire body and most organ systems, the disease most often involves inflammation and consequent injury to the joints, skin, kidney, brain, the membranes in body cavities, lung, heart, and gastrointestinal tract. An individual with SLE often experiences unpredictable acute episodes or “outbreaks” and equally unexpected remissions. The pathologic hallmark of the disease is recurrent, widespread, and diverse vascular lesions resembling a rash or changes on the surface of the skin.
The prevalence of SLE in the United States is an issue of some debate. Estimates of prevalence range from 250,000 to 2,000,000 persons. Although reported in both the extremely old and the extremely young, the disease mainly affects women of childbearing age. Among children SLE is three times more common in females than in males. In the 60% of SLE patients who experience the onset of this disease between puberty and the fourth decade of life, the female to male ratio is 9:1. Thereafter, the female preponderance again falls to that observed in prepubescent children (i.e. 3:1). In addition, the disorder appears to be three times more common in persons of African and Asian descent than in persons of Caucasian descent.
The etiology of SLE remains unknown. A genetic predisposition, the systemic proliferation of sex hormones, and various environmental triggers, such as viral infections have been suggested to play a role in triggering the aberrant immune responses that typify the disease. A role for genetics is suggested by the increased percentage of two histocompatibility antigens, HLA-DR2 and HLA-DR3, in patients with SLE. In addition, there is an increased frequency of the extended haplotypes HLA-A1, B8, and DR3 in affected individuals. The role of heredity is further supported by the concordance for this illness among monozygotic twins. The polygenic nature, however, of this genetic predisposition as well as the contribution of environmental factors is suggested by the concordance rate, which is only moderate and reported to be between 25% and 60%.
The precise initiating etiology of SLE is unknown. However, it is generally accepted that most of the clinical manifestations of the disease are caused either directly or indirectly by autoantibody production and the subsequent formation of pathogenic immune complexes. These autoantibodies, which are produced by dysregulated B lymphocytes, have distinct specificities recognizing discrete nuclear autoantigens including, among others, DNA, nucleosomes and subnucleosomes. Certain RNA/protein complexes including the Sm antigen and small nuclear ribonucleoproteins (snRNP) are additional characteristic autoantigenic specificities. The pathogenic immune complexes are formed by binding of the autoantibodies to their respective nuclear autoantigens.
Autoantibodies in SLE often circulate as immune complexes (IC) bound with their respective autoantigens. Chromatin or chromatin fragments such as DNA, nucleosomes or subnucleosome particles are especially common autoantigenic specificities in both mice and humans (Tan, E. Adv. Immunol. 44, 93-151 (1989); Monestier and Novick, Mol. Immunol. 33: 89-99., 1996)
The central goals in the treatment of SLE, therefore, are either to attempt to suppress the dysfunctional B lymphocytes thereby decreasing the production of autoantibody or, to attempt to diminish the pathogenicity of the immune complexes once they have formed. At present these goals can only be achieved, and often incompletely so, by the use of intensive systemic immunosuppressive drug therapy using drugs such as cortisone, azathioprine, hydroxychloroquine and cyclophosphamide. These therapies are associated with many serious and undesirable side-effects including infections, infertility, retinopathy and cancer. Therefore, new treatments for SLE, and other autoimmune diseases, would be desirable.